Modulation of sodium activated potassium channels (K Na ) by p38 map kinase
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Pain signaling is sensed by dorsal root ganglion (DRG) neurons. After nerve injury, DRG neurons can become hyperexcitable and generate a chronic and painful phenotype known as neuropathic pain. The exact underlying cellular mechanisms precipitating neuropathic pain are unclear, but altered ion channel properties are key in determining DRG neuronal hyperexcitability. One class of ion channels known as the sodium activated potassium (K Na ) channels have been shown to regulate the resting membrane potential (RMP) and control firing accommodation in these neurons, and could very well be a central player in neuropathic pain. Multiple lines of evidence have indicated that p38 Mitogen Activated Protein Kinase (p38 MAPK) activity is important during neuropathic pain. Indeed, it has been recently shown that p38 MAPK facilitates neuronal regeneration after nerve crush of the sciatic nerve. Because of the roles of p38 MAPK in neuropathy and K Na channel involvement in DRG neuronal excitability, I sought to determine whether p38 MAPK regulates K Na channels in DRG neurons. I used anisomycin, a p38 MAPK activator, and a p38 MAPK Inhibitor to study the effects of p38 MAPK on potassium currents in rat embryonic DRG neurons and Slack K Na channels in heterologous expression systems. I show that K Na currents are upregulated by p38 MAPK in DRG neurons; Slack currents are also modulated by p38 MAPK. Using site-directed mutagenesis, I have shown that mutating one of Slack's putative p38 phosphorylation sites to glutamic acid significantly speeds up activation kinetics. These results suggest that K Na channels regulated by p38 MAPK in DRG neurons act to prevent hyperexcitability and may aid in the neuronal regeneration process after nerve injury.